Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

Julian Petersen; Shane C. Wright; David Rodríguez; Pierre Matricon; Noa Lahav; Aviv Vromen; Assaf Friedler; Johan Strömqvist; Stefan Wennmalm; Jens Carlsson; Gunnar Schulte

doi:10.1038/s41467-017-00253-9

Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

Julian Petersen, Shane C. Wright, David Rodríguez, Pierre Matricon, Noa Lahav, Aviv Vromen, Assaf Friedler, Johan Strömqvist, Stefan Wennmalm, Jens Carlsson, Gunnar Schulte^*

^*Corresponding author for this work

Institute of Chemistry

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD₆) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD₆ dimerizes and that the dimer interface of FZD₆ is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD₆ mutant indicates that dimer dissociation is an integral part of FZD₆ signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.

Original language	American English
Article number	226
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00253-9
State	Published - 1 Dec 2017

Bibliographical note

Funding Information:
Nevin Lambert is kindly acknowledged for his scientific input and help in creating the stoichiometer construct. We thank Marin M. Jukic for his input in statistical analysis. The work was supported by grants from Karolinska Institutet, the Science for Life Laboratory, the Swedish Research Council (2007-2769, 2007-5595, 2011-2435, 2013- 5708, 2015-02899), the Swedish Cancer Society (CAN2011/690, CAN2014/659), the Knut & Alice Wallenberg Foundation (KAW2008.0149; 2008.0139), the Swedish Foundation for Strategic Research (ICA10-0098), the Board of Doctoral Education at Karolinska Institutet (JP), Engkvist's Foundations, Foundation Lars Hiertas Minne, Swedish Royal Academy of Sciences/Foundation Hierta-Retzius Fond, the Czech Science Foundation (13-32990S), the Program "KI-MU" (CZ.1.07/2.3.00/20.0180) co-financed from European Social Fund and the state budget of the Czech Republic and the Marie Curie ITN WntsApp (Grant no.608180; www.wntsapp.eu). D.R. is funded by a postdoctoral fellowship from the Sven och Lilly Lawski Foundation (N2014-0049). Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC) and National Supercomputer Centre (NSC) in Linköping. J.C. and D.R. participate in the European COST Action CM1207 (GLISTEN). A.F. is supported by a grant from the Israel Science Foundation.

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© 2017 The Author(s).

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title = "Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling",

abstract = "G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.",

author = "Julian Petersen and Wright, {Shane C.} and David Rodr{\'i}guez and Pierre Matricon and Noa Lahav and Aviv Vromen and Assaf Friedler and Johan Str{\"o}mqvist and Stefan Wennmalm and Jens Carlsson and Gunnar Schulte",

note = "Funding Information: Nevin Lambert is kindly acknowledged for his scientific input and help in creating the stoichiometer construct. We thank Marin M. Jukic for his input in statistical analysis. The work was supported by grants from Karolinska Institutet, the Science for Life Laboratory, the Swedish Research Council (2007-2769, 2007-5595, 2011-2435, 2013- 5708, 2015-02899), the Swedish Cancer Society (CAN2011/690, CAN2014/659), the Knut & Alice Wallenberg Foundation (KAW2008.0149; 2008.0139), the Swedish Foundation for Strategic Research (ICA10-0098), the Board of Doctoral Education at Karolinska Institutet (JP), Engkvist's Foundations, Foundation Lars Hiertas Minne, Swedish Royal Academy of Sciences/Foundation Hierta-Retzius Fond, the Czech Science Foundation (13-32990S), the Program {"}KI-MU{"} (CZ.1.07/2.3.00/20.0180) co-financed from European Social Fund and the state budget of the Czech Republic and the Marie Curie ITN WntsApp (Grant no.608180; www.wntsapp.eu). D.R. is funded by a postdoctoral fellowship from the Sven och Lilly Lawski Foundation (N2014-0049). Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC) and National Supercomputer Centre (NSC) in Link{\"o}ping. J.C. and D.R. participate in the European COST Action CM1207 (GLISTEN). A.F. is supported by a grant from the Israel Science Foundation. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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doi = "10.1038/s41467-017-00253-9",

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AU - Petersen, Julian

AU - Wright, Shane C.

AU - Rodríguez, David

AU - Matricon, Pierre

AU - Lahav, Noa

AU - Vromen, Aviv

AU - Friedler, Assaf

AU - Strömqvist, Johan

AU - Wennmalm, Stefan

AU - Carlsson, Jens

AU - Schulte, Gunnar

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PY - 2017/12/1

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N2 - G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.

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Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

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